不止是肺？研究团队发现新冠病毒危害肾脏！

全文翻译：菁菁

研究小组从患者样本中分离出的严重感染SARS-CoV-2病毒颗粒（红色）的细胞（蓝色），上图为其彩色扫描电子显微照片。

肺是COVID-19的细胞因子风暴的常见靶标，肾脏也是如此。当前，美国大约四分之一的成年人患有糖尿病，这些人因为糖尿病性肾脏疾病而面临较高的病毒死亡风险。

但是，为什么肾脏对冠状病毒具有较高的吸引力呢？

由肾脏临床医生，生物信息学家，分子生物学家，病理学家和病毒学家组成的研究小组最近在《Kidney International》上发表论文。论文指出，某些肾脏细胞表面有一种蛋白，名为血管紧张素转化酶2（ACE2）。这种蛋白是COVID-19进入肾脏的主要受体，并促使激活不受控制的免疫反应。

同时，这种蛋白也负责病毒的复制，加重病人病情，减慢痊愈时间。

由于细胞中ACE2表达水平的升高与严重COVID-19疾病的风险升高相关，密歇根大学研究作者、肾脏病专家Matthias Kretzler医师希望了解哪些肾细胞使该蛋白水平升高，以及肾细胞的分子过程是否与COVID-19患者类似。

使用普林斯顿大学研究作者Olga TroyansKaya博士开发的机器学习技术，研究人员能够识别在三个不同受试者组中产生较高ACE2表达水平的基因组，并对其进行分类：健康的活体肾脏供体（18位参与者），患有糖尿病性肾病的患者（44位参与者）和住院的COVID-19患者（13位参与者）。

在分析了三组中超过110，000个不同细胞后，Kretzler及其团队确定了导致ACE2水平升高的分子网络。

Kretzler说：“表征这些分子过程，可能有助于科学家快速识别和开发疗法，以减轻患者患严重疾病的风险，并防止COVID-19感染损害肾脏。”

三组受试者存在一些分子相似性，但有一点吸引了研究人员的注意：有的细胞表达了近端小管中专门转运上皮细胞的标志物，ACE2主要在这些细胞中表达。在肾脏过滤过程中，这一区域的功能是吸收营养。

机器学习技术的应用

机器学习技术通过分析健康肾脏和糖尿病性肾病患者的肾脏活检样本，以及从COVID-19患者的尿液样本中提取的肾脏细胞，确定了表达ACE2的肾脏细胞以及这些细胞的特征。表达病毒受体ACE2的细胞已经被病毒“锁定并搭载”，研究还发现了许多其他与ACE2一起在感染过程中与病毒相互作用的蛋白质。

这一发现不仅适用于感染COVID-19的患者，而且适用于糖尿病患者的肾脏。当将COVID-19患者的肾脏细胞与糖尿病性肾病患者的肾脏细胞进行比较时，两种分子中都激活了类似的分子过程，从而触发了严重的COVID-19疾病。

Kretzler说：“本质上，糖尿病性肾病会使肾脏细胞更容易感染COVID-19。结合COVID-19及其炎性性质，可能会发生严重的肝肾损害。”

我们知道和不知道的

研究发现近端小管上皮细胞与COVID-19疾病的严重性有关，这至关重要，为探索COVID-19及其相关肾脏损伤的新疗法打开了一扇门。

“在这项研究之前，我们不确定通常用于治疗高血压和糖尿病性肾病的药物是否会增加COVID-19感染的风险。我的同事和患者对这些药物如何影响肾脏ACE2非常关注。”Kretzler说。

现在，研究小组得出结论，这些药物不会损害糖尿病性肾病患者的健康，从而使患者放心，继续服用这些救命药。

进一步的研究需要研究同时患有糖尿病性肾病和COVID-19的人群。Kretzler表示这些行动正在进行中。

Kretzler说：“为了帮助全球应对COVID-19的研究，我们将数据提供给世界各地的科学家，以便他们可以利用这些信息来探索治疗COVID-19患者的新疗法。我们的的团队现在专注于研究对COVID-19患者的治疗如何影响肾细胞，因此我们可以为受到持续COVID-19流行影响的肾病患者提供最佳药物。”

【英文原文】

Research team discovers molecularprocesses in kidney cells that attract andfeed COVID-19

Colorized scanning electron micrograph of a cell (blue)heavily infected with SARS-CoV-2 virus particles (red),isolated from a patient sample. Image captured at theNIAID Integrated Research Facility (IRF) in Fort Detrick,Maryland. Credit: NIAID

Although the lungs are a common target forCOVID-19's cytokine storm, so are the kidneys,making the 1 in 4 U.S. adults with diabetesresulting in diabetic kidney disease at increasedrisk for virus mortality. 

But why are the kidneys so attractive to the coronavirus?

Recently published in Kidney International, a national research team made up of kidneyclinicians, bioinformaticians, a molecular biologist,pathologist and virologist found that a protein onthe surface of some kidney cells, called angiotensinconverting enzyme 2 (ACE2), is the primaryCOVID-19 entry receptor and aids in the activationof its uncontrolled immune response.

It also is responsible for the virus' duplication,leaving patients sicker, longer.

Since higher levels of ACE2 expression on cellscorrelates with higher risk of serious COVID-19illness, Matthias Kretzler, M.D., a study author andnephrologist at Michigan Medicine, sought out tolearn more about which kidney cells createelevated levels of this protein and why, as well as ifthe molecular process of the vulnerable cells issimilar to those in patients with COVID-19.

Using machine learning technology developed bystudy author Olga Troyanskaya, Ph.D., from Princeton University, the researchers were able toidentify and categorize groups of genes thatproduced higher ACE2 expression levels in threedifferent subject groups: healthy, living kidneydonors (18 participants), those with diabetic kidneydisease (44 participants) and those hospitalizedwith COVID-19 (13 participants.)

After analyzing more than 110,000 different cells inthe three groups, Kretzler and the team identifiednetworks of molecules that result in higher levels ofACE2."

Being able to characterize these molecularprocesses may help scientists quickly identify anddevelop therapies to lessen the risk of seriousillness for patients, or even prevent COVID-19infection from damaging the kidney," Kretzler says.

The groups shared a few molecular similarities, butone would become the focus of the researchers:ACE2 was predominantly expressed in cells thatalso expressed markers of specialized transportepithelial cells in the proximal tubules.

This area of the kidney is responsible forreabsorbing nutrients during the kidney's filtrationprocess.

Machine Learning

Using kidney biopsies from the healthy kidneys andthose with diabetic kidney disease, and kidney cellsretrieved from the urine samples of COVID-19patients, the machine learning technology allowedthe research team to pinpoint in what kidney cellsACE2 is found and what characteristics these cellshave.

Cells that express the virus receptor, ACE2, werefound to be "locked and loaded" for the virus,meaning many other proteins are found with ACE2which interact with viruses during infection.

This wasn't only true in the COVID-19 infectedpatients, but also in kidneys from patients withdiabetes. When comparing the kidney cells ofCOVID-19 patients with those with diabetic kidneydisease, similar molecular processes wereactivated in both that would trigger severeCOVID-19 illness.

"Diabetic kidney disease, by nature, primes kidneycells in a way that can make them vulnerable toCOVID-19," Kretzler says. "In conjunction withCOVID-19 and its inflammatory nature, seriouskidney damage can occur."

know and don't know

Discovering the importance of the proximal tubulesepithelial cells in its relation to the severity ofCOVID-19 illness opens a door for noveltherapeutics to address COVID-19 and its relatedkidney injury."

We weren't sure before this study if medicationscommonly used to treat hypertension and diabetickidney disease increase the risk of COVID-19infection. There was a serious concern fromcolleagues and my patients about how thesemedications affect ACE2 in the kidney," Kretzlersays.

Now, the team can confidently conclude thesemedications won't harm those with diabetic kidneydisease, providing reassurance for patients tocontinue to take these live saving medicines.

However, further studies need to look at apopulation that has both diabetic kidney diseaseand COVID-19. Kretzler confirms these areunderway."

To help in the global research response toCOVID-19, we made our data available to scientistsaround the world so that they can use theinformation from our patients to help identify novelways to treat patients in the pandemic," Kretzlersays. "Our team is focused now on learning howtreatments given to COVID-19 patients affectkidney cells, so we can offer the best medicationsto patients with COVID-19 and kidney disease inthe ongoing pandemic."

参考文献

Rajasree Menon et al, SARS-CoV-2 receptor networks in diabetic and COVID-19associated kidney disease, Kidney International(2020). DOI: 10.1016/j.kint.2020.09.015

本文内容由振东健康网整理发布